Prolonged clinical remissions in patients with relapsed or refractory follicular lymphoma treated with autologous stem cell transplantation incorporating rituximab.

Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed­median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Analysis of a hot spot for DNA insertion suggests a mechanism for Ig switch recombination.

We recently reported that transfected DNA inserts into the VDJ-Cmu intron much more frequently than into average DNA, and that insertion within this intron occurs preferentially into the switch region. To gain information about the mechanisms involved in DNA insertion, we sequenced the 5' and 3' junctions of typical transformants. Although the junction sequences did not indicate a preferred insertion motif within the switch region, our results suggest that joining of the transfected and chromosomal DNAs is facilitated by short regions of identity. Our analysis of the insertions into the non-switch part of the intron suggests that breakage of the chromosomal DNA occurs preferentially at sites that are flanked by short complementary sequences. This correlation suggests that the self-complementary DNA might form short stem-loops, which, in turn, are prone to enzymatic cleavage and thus facilitate the insertion of transfected DNA. A model is proposed in which this effect can account for both the higher than average frequency of insertion into the VDJ-Cmu intron and the preference for the switch region within this intron. An extension of this model is proposed to explain why the repetitive switch regions are the preferred breakage/rejoining sites for isotype switch rearrangements.